Muscle pain, due to mechanical causes, is pervasive in our lives. Acutely, it is initiated by mechanical stimulation, at tissue threatening (i.e., noxious) magnitudes, of specialized neurons innervating muscle called 'nociceptors'. The treatment of painful muscle conditions results in enormous expenditure of financial resources in the United States. Yet, our understanding of the underlying, peripheral, neural mechanisms that give rise to muscle pain due to mechanical causes if very limited. There are no quantitative biochemical studies of the neurophysiology of muscle or tendon nociceptors that encode noxious, mechanical stimuli. The relevant state of the mechanical stimulus at the level of the receptor has not been studied experimentally. Further, there are no robust mechanical models of how these sensory receptors are activated in situ. Hence, we are currently able to quantitatively predict the types of amounts of physical activity that will result in muscle pain in healthy individuals, much less those already injured or diseased. Nor can we predict the neurophysiological response to specific injuries. The aims of this research project will elucidate neural mechanisms that encode noxious, mechanical stimuli in muscle and that ultimately result in muscle pain. A first-order model will be developed to describe the activation of a nociceptor population in skeletal muscle. The 2 Specific Aims of this project are to determine 1) the relevant mechanical state that activates muscle and tendon nociceptors during stretch and passive compression; (2) how populations of muscle nociceptors encode noxious indentation. To accomplish these aims, the neural responses of single, nociceptors innervating tendon and muscle will be recording while simultaneously measuring the mechanical state that stimulates those neurons. The rat gracilis muscle will be used as a model system. Nociceptors innervating muscle or its tendons, do not experience the externally applied force or displacement during a noxious mechanical load. Rather, they experience the internally developed local stress (related to force) and/or local strain (related to displacement). In these experiments, the local stress and strain will be independently measured at the receptor endings of identified nociceptors. Nociceptors will be stimulated with noxious magnitudes of passive stretch and/or compression. A biomechanical model of single nociceptors and a nociceptor population response to noxious mechanical stimuli will be created.